Cancer chemoprevention is defined as the use of natural or synthetic agents, in combination or alone, to inhibit, delay, or reverse the carcinogenic process and is recognized as a very promising area of cancer research. Numerous epidemiological studies have shown the strong correlation between frequent consumption of fresh fruits and vegetables and a decreased cancer risk. With a food-based approach to cancer chemoprevention, emphasis is placed on the potential for complex mixtures of preventive agents in whole food to inhibit multiple processes of carcinogenesis. In support of this approach, several preclinical animal studies have been conducted that demonstrate the remarkable chemopreventive activity of black raspberries on chemically-induced aerodigestive tract tumor development, including oral, esophagus, and colon. While this chemopreventive phenomenon is striking in animal models of cancer, the chemopreventive potential of black raspberries on human cancer development remains unstudied. The present proposal is fundamentally translational in nature and strives to extend the chemopreventive assessment of this fruit to the problem of human oral cancer. Preliminary studies by us have shown that an extract of lyophilized black raspberries (LBR) dramatically inhibits the in vitro proliferation of cells derived from a human oral squamous cell carcinoma, suggesting that the chemoprevention of oral cancer by LBR components in vivo is possible. We therefore hypothesize that LBR will modulate the expression of critical genes associated with key biological pathways which may ultimately result in the inhibition, delay or reversal of the carcinogenic process. We will first identify changes in the global gene expression profiles in response to black raspberry treatment of human oral cancer cells in vitro (Specific Aim 1) and then determine the ability of black raspberries to modulate similar gene expression profiles in primary human oral cancer cells in vivo through a Phase 1B study (Specific Aim 2). These novel studies will be the first to examine the chemopreventive and molecular effects of a natural food product on human oral tumorigenesis. Additionally, these data will provide a suitable foundation from which future chemopreventive studies using LBR or other chemopreventive agents that target responsive genes will be conducted in post-surgical patients or those presenting with premalignant lesions.